tbuckley/cabot-search huggingface dataset:
Cell Membranes from Tumor‐Tropic MSCs Screened by a Microfluidic Chip for Drug Nanoparticles Encapsulation and Cancer Targeted Therapy
Authors: Yizuo Song, Xin Shou, Bo Sheng, Jie Mei, Keqing Shi, Luoran Shang, Xueqiong Zhu
Journal: Advanced Healthcare Materials (2023)

Abstract Nanoparticles (NPs)‐based drug carriers are effective in reducing systemic toxicity and drug resistance for chemotherapy, and an emerging trend focuses on integrating cell membranes with nanomedicines for tumor targeting. Mesenchymal stem cells (MSCs) are promising candidates due to their unique tropism toward cancer cells, yet the tumor‐tropic abilities can differ for MSCs sourced from different tissues. Here, a multichannel microfluidic chip to screen different sourced MSCs with the greatest tropism toward cervical cancer cells is developed. Based on this, the cell membranes from the chorionic plate‐derived MSC are isolated and membrane‐camouflaged platinum prodrug composite NPs for cervical cancer treatment are prepared. Results demonstrate that the composite NPs can effectively target tumor sites and have a therapeutic effect both in vitro and in vivo. It is believed that the present microfluidic platform is a powerful tool for cell screening and tumor‐on‐a‐chip studies, and the derived nanodelivery system represents the great value of cell membrane‐camouflaged nanomedicine for targeted cancer therapy.
Familial clustering of intrahepatic cholestasis of pregnancy: A nationwide population-based study in Denmark
Authors: Jiong Li, Jiawen Chen, Priscilla Ming Yi Lee, Jun Zhang, Fei Li, Tai Ren
Journal: Hepatology (2023)

Genetics plays a role in the pathogenesis of intrahepatic cholestasis of pregnancy (ICP); however, empirical evidence on familial clustering of ICP is scarce. We aimed to assess the extent of familial recurrence of ICP.This population-based cohort study included all 668,461 primiparous women who gave birth between 1995 and 2018 in Denmark. Women diagnosed with ICP were included to the index cohort. Kinship with index women was determined with the Danish Civil Registration System. Log-binomial regression was used to calculate the relative recurrence risk (RRR) of ICP in relatives of index women. A total of 6722 (1.0%) primiparous women were diagnosed with ICP. In co-twins (n=57), first-degree (n=2279), second-degree (n=1373), and third-degree (n=1758) relatives of the index women, the incidence of ICP reached 5.3%, 2.6%, 0.7%, and 1.4%, respectively, corresponding to adjusted RRRs of 4.82 (95% CI, 1.60-14.48), 2.54 (1.98-3.26), 0.81 (0.44-1.51), and 1.15 (0.77-1.71), respectively. The first-degree relatives of women who had recurrent ICP or first-trimester ICP seemed to be at higher risks [RRR, 4.30 (2.85-6.48), 3.04 (1.93-4.77), respectively]. A minor increased risk was observed in nonbiological relatives [RRR, 1.35 (1.05-1.73); n=4274, including women's full-brothers' partner and women's husbands' full sisters].Co-twins and first-degree relatives of ICP patients were at ~5- and ~2.5-fold increased risk of ICP, respectively. No increased risk was observed in second-degree and third-degree relatives. Recurrent ICP and first-trimester ICP might indicate a higher degree of family clustering. Further investigation is needed to investigate the increased risk of ICP in nonbiological relatives.
Reply
Authors: Gyongyi Szabo, Mack C. Mitchell, Srinivasan Dasarathy, Craig McClain
Journal: Hepatology (2023)

We appreciate the points made by Malkebe et al in their Letter to the Editor about survival in placebo-treated patients with severe alcohol-associated hepatitis (AH). Clinical trial design in AH has been challenging due to several factors. First, many physicians and patients as well as institutional review boards are reluctant to use placebo trials in light of the demonstrated benefits of steroids, the current standard of care, in improving 30-day survival in clinical trials of patients with severe AH. Second, overall survival in AH appears to be improving in recent years for unclear reasons. Some of the contributing factors may include advances in supportive care in intensive care unit and hospital settings as well as the practice of a holistic approach in the management of AH patients that includes targeted management of the component of alcohol use disorder to support long-term abstinence. A recent presentation at the American Association for the Study of Liver Diseases annual meeting showed that survival in 73 patients treated with prednisone was 97% for 30 days and 90% for 90 days, both of which are much better than the survival of "placebo-treated" patients noted by Malkebe et al (late-breaker abstract). We also need to point out that our study with anakinra did not include a formal placebo arm (Reference: Hepatology paper). Our study compared the combination of anakinra plus pentoxifylline plus zinc versus methylprednisolone (standard of care treatment). To maintain the blinding on the 3-drug regimen, an anakinra-matched placebo and a pentoxifylline-matched placebo were added to the methylprednisolone treatment arm. There was no study aim with only a placebo without drug intervention. We agree with Melkebeke et al that future well-designed studies will likely need to include large cohorts of patients to assure statistically meaningful results. Newer approaches using adaptive clinical trial designs could reduce the number of patients needed to include to assure results with statistically significant outcomes. However, the benefits of corticosteroids in recent trials may limit enthusiasm for a placebo-only standard of care arm in future trial design.
Targeting YAP-mediated HSC death susceptibility and senescence for treatment of liver fibrosis
Authors: Kuo Du, Raquel Maeso-Díaz, Seh Hoon Oh, Ergang Wang, Tianyi Chen, Christopher Pan, Kun Xiang, Rajesh Kumar Dutta, Xiao-Fan Wang, Jen-Tsan Chi, Anna Mae Diehl
Journal: Hepatology (2023)

Background and Aims: Liver fibrosis results from the accumulation of myofibroblasts (MFs) derived from quiescent HSCs, and yes-associated protein (YAP) controls this state transition. Although fibrosis is also influenced by HSC death and senescence, whether YAP regulates these processes and whether this could be leveraged to treat liver fibrosis are unknown. Approach and Results: YAP activity was manipulated in MF-HSCs to determine how YAP impacts susceptibility to pro-apoptotic senolytic agents or ferroptosis. Effects of senescence on YAP activity and susceptibility to apoptosis versus ferroptosis were also examined. CCl 4 -treated mice were treated with a ferroptosis inducer or pro-apoptotic senolytic to determine the effects on liver fibrosis. YAP was conditionally disrupted in MFs to determine how YAP activity in MF-HSC affects liver fibrosis in mouse models. Silencing YAP in cultured MF-HSCs induced HSC senescence and vulnerability to senolytics, and promoted ferroptosis resistance. Conversely, inducing HSC senescence suppressed YAP activity, increased sensitivity to senolytics, and decreased sensitivity to ferroptosis. Single-cell analysis of HSCs from fibrotic livers revealed heterogeneous sensitivity to ferroptosis, apoptosis, and senescence. In mice with chronic liver injury, neither the ferroptosis inducer nor senolytic improved fibrosis. However, selectively depleting YAP in MF-HSCs induced senescence and decreased liver injury and fibrosis. Conclusion: YAP determines whether MF-HSCs remain activated or become senescent. By regulating this state transition, Yap controls both HSC fibrogenic activity and susceptibility to distinct mechanisms for cell death. MF-HSC-specific YAP depletion induces senescence and protects injured livers from fibrosis. Clarifying determinants of HSC YAP activity may facilitate the development of novel anti-fibrotic therapies.
Lean individuals with NAFLD have more severe liver disease and poorer clinical outcomes (NASH-CO Study)
Authors: Oumarou Nabi, Nathanaël Lapidus, Jerome Boursier, Victor de Ledinghen, Jean-Michel Petit, Sofiane Kab, Adeline Renuy, Marie Zins, Karine Lacombe, Lawrence Serfaty
Journal: Hepatology (2023)

The severity of liver injury and clinical outcomes in lean individuals with NAFLD is a subject of debate and very few studies have been performed in the general population. The aim of this study was to compare subject characteristics and mortality between lean and nonlean NAFLD in a community setting.The study population included 169,303 participants from the nationwide Constances cohort. Subjects with excessive alcohol consumption, viral hepatitis, or other liver diseases were excluded and 137,206 subjects were analyzed. The diagnosis of NAFLD and fibrosis was performed using the Fatty Liver Index and the Forns Index. The median follow-up was 3.58 years. The prevalence of NAFLD was 5.3% (95% CI: 5.2-5.4) in lean subjects, while 16.3% (95% CI: 15.7-16.8) of NAFLD subjects were lean. Despite their better metabolic profile, the prevalence of advanced fibrosis was significantly higher in lean than in nonlean NAFLD (3.7% vs. 1.7%, respectively, p < 0.01). Among NAFLD subjects and after adjustment for demographics, metabolic risk factors and lifestyle, lean status was associated with advanced fibrosis (OR=1.26, 95% CI: 1.20-1.65, p = 0.005), an increased risk of liver-related events (adjusted HR=5.84, 95% CI: 4.03-8.46), chronic kidney disease (adjusted HR=2.49, 95% CI: 1.49-4.16), and overall mortality (adjusted HR=3.01, 95% CI: 2.21-4.11). Liver-related events and overall mortality were related to the severity of fibrosis, both in lean and nonlean NAFLD subjects, whatever the usual risk factors.This study in a large community-based cohort confirms that NAFLD in lean subjects is more severe for fibrosis, the progression of liver disease, chronic kidney disease, and overall mortality.
Human liver organoids: From generation to applications
Authors: Marta B. Afonso, Vanda Marques, Saskia W.C. van Mil, Cecilia M.P. Rodrigues
Journal: Hepatology (2023)

In the last decade, research into human hepatology has been revolutionized by the development of mini human livers in a dish. These liver organoids are formed by self-organizing stem cells and resemble their native counterparts in cellular content, multicellular architecture, and functional features. Liver organoids can be derived from the liver tissue or pluripotent stem cells generated from a skin biopsy, blood cells, or renal epithelial cells present in urine. With the development of liver organoids, a large part of previous hurdles in modeling the human liver is likely to be solved, enabling possibilities to better model liver disease, improve (personalized) drug testing, and advance bioengineering options. In this review, we address strategies to generate and use organoids in human liver disease modeling, followed by a discussion of their potential application in drug development and therapeutics, as well as their strengths and limitations.
Smooth Muscle Mineralocorticoid Receptor Promotes Hypertension After Preeclampsia
Authors: Lauren A. Biwer, Qing Lu, Jaime Ibarrola, Alec Stepanian, Joshua J. Man, Brigett V. Carvajal, Nicholas D. Camarda, Zsuzsanna Zsengeller, Geraldine Skurnik, Ellen W. Seely, S. Ananth Karumanchi, Iris Z. Jaffe
Journal: Circulation Research (2023)

Preeclampsia is a syndrome of high blood pressure (BP) with end organ damage in late pregnancy that is associated with high circulating soluble VEGF receptor (sFlt1 [soluble Fms-like tyrosine kinase 1]). Women exposed to preeclampsia have a substantially increased risk of hypertension after pregnancy, but the mechanism remains unknown, leaving a missed interventional opportunity. After preeclampsia, women have enhanced sensitivity to hypertensive stress. Since smooth muscle cell mineralocorticoid receptors (SMC-MR) are activated by hypertensive stimuli, we hypothesized that high sFlt1 exposure in pregnancy induces a postpartum state of enhanced SMC-MR responsiveness.
A New Transthyretin Mutation Associated with Amyloidotic Vitreous Opacities
Authors: Martha Skinner, Jennifer Harding, Ilze Skare, Lee Anna Jones, Alan S. Cohen, Aubrey Milunsky, James Skare
Journal: Ophthalmology (1992)

An inherited type of amyloidosis was suspected in an individual of Italian descent who presented with vitreous opacities. Although no family history of amyloidosis was apparent, the patient's transthyretin gene was examined and found not to possess any of the known transthyretin mutations. Complete DNA sequencing revealed a substitution of adenine for thymine in the second base of codon 84 causing an amino acid change of asparagine for isoleucine. The mutation was confirmed by demonstrating the loss of an Sfa N1 restriction endonuclease site. Allele-specific DNA amplification by polymerase chain reaction also was used to confirm the mutation. Either of these tests can be used for diagnosis. Asparagine 84 represents the second mutation associated with amyloidosis to occur at codon 84. An inherited type of amyloidosis was suspected in an individual of Italian descent who presented with vitreous opacities. Although no family history of amyloidosis was apparent, the patient's transthyretin gene was examined and found not to possess any of the known transthyretin mutations. Complete DNA sequencing revealed a substitution of adenine for thymine in the second base of codon 84 causing an amino acid change of asparagine for isoleucine. The mutation was confirmed by demonstrating the loss of an Sfa N1 restriction endonuclease site. Allele-specific DNA amplification by polymerase chain reaction also was used to confirm the mutation. Either of these tests can be used for diagnosis. Asparagine 84 represents the second mutation associated with amyloidosis to occur at codon 84.
Pitfalls and opportunities for applying latent variables in single-cell eQTL analyses
Authors: Angli Xue, Seyhan Yazar, Drew Neavin, Joseph E. Powell
Journal: Genome biology (2023)

Abstract Using latent variables in gene expression data can help correct unobserved confounders and increase statistical power for expression quantitative trait Loci (eQTL) detection. The probabilistic estimation of expression residuals (PEER) and principal component analysis (PCA) are widely used methods that can remove unwanted variation and improve eQTL discovery power in bulk RNA-seq analysis. However, their performance has not been evaluated extensively in single-cell eQTL analysis, especially for different cell types. Potential challenges arise due to the structure of single-cell RNA-seq data, including sparsity, skewness, and mean-variance relationship. Here, we show by a series of analyses that PEER and PCA require additional quality control and data transformation steps on the pseudo-bulk matrix to obtain valid latent variables; otherwise, it can result in highly correlated factors (Pearson's correlation r = 0.63 ~ 0.99). Incorporating valid PFs/PCs in the eQTL association model would identify 1.7 ~ 13.3% more eGenes. Sensitivity analysis showed that the pattern of change between the number of eGenes detected and fitted PFs/PCs varied significantly in different cell types. In addition, using highly variable genes to generate latent variables could achieve similar eGenes discovery power as using all genes but save considerable computational resources (~ 6.2-fold faster).
Outcome prediction by the 2022 European LeukemiaNet genetic-risk classification for adults with acute myeloid leukemia: an Alliance study
Authors: Krzysztof Mrózek, Jessica Kohlschmidt, James S. Blachly, Deedra Nicolet, Andrew J. Carroll, Kellie J. Archer, Alice S. Mims, Karilyn T. Larkin, Shelley Orwick, Christopher C. Oakes, Jonathan E. Kolitz, Bayard L. Powell, William G. Blum, Guido Marcucci, Maria R. Baer, Geoffrey L. Uy, Wendy Stock, John C. Byrd, Ann-Kathrin Eisfeld
Journal: Leukemia (2023)

Abstract Recently, the European LeukemiaNet (ELN) revised its genetic-risk classification of acute myeloid leukemia (AML). We categorized 1637 adults with AML treated with cytarabine/anthracycline regimens according to the 2022 and 2017 ELN classifications. Compared with the 2017 ELN classification, 2022 favorable group decreased from 40% to 35% and adverse group increased from 37% to 41% of patients. The 2022 genetic-risk groups seemed to accurately reflect treatment outcomes in all patients and patients aged &lt;60 years, but in patients aged ≥60 years, relapse rates, disease-free (DFS) and overall (OS) survival were not significantly different between intermediate and adverse groups. In younger African-American patients, DFS and OS did not differ between intermediate-risk and adverse-risk patients nor did DFS between favorable and intermediate groups. In Hispanic patients, DFS and OS did not differ between favorable and intermediate groups. Outcome prediction abilities of 2022 and 2017 ELN classifications were similar. Among favorable-risk patients, myelodysplasia-related mutations did not affect patients with CEBPA bZIP mutations or core-binding factor AML, but changed risk assignment of NPM1 -mutated/ FLT3 -ITD-negative patients to intermediate. NPM1 -mutated patients with adverse-risk cytogenetic abnormalities were closer prognostically to the intermediate than adverse group. Our analyses both confirm and challenge prognostic significance of some of the newly added markers.
Abatacept/Ruxolitinib and Screening for Concomitant Respiratory Muscle Failure to Mitigate Fatality of Immune-Checkpoint Inhibitor Myocarditis
Authors: Joe-Elie Salem, Marie Bretagne, Baptiste Abbar, Sarah Leonard-Louis, Stéphane Ederhy, Alban Redheuil, Samia Boussouar, Lee S. Nguyen, Adrien Procureur, Frederic Stein, Charlotte Fenioux, Perrine Devos, Paul Gougis, Martin Dres, Alexandre Demoule, Dimitri Psimaras, Timothee Lenglet, Thierry Maisonobe, Marc Pineton De Chambrun, Guillaume Hekimian, Christian Straus, Jesus Gonzalez-Bermejo, David Klatzmann, Aude Rigolet, Perrine Guillaume-Jugnot, Nicolas Champtiaux, Olivier Benveniste, Nicolas Weiss, Samir Saheb, Philippe Rouvier, Isabelle Plu, Estelle Gandjbakhch, Mathieu Kerneis, Nadjib Hammoudi, Noel Zahr, Claudia Llontop, Capucine Morelot-Panzini, Lorenz Lehmann, Juan Qin, Javid J. Moslehi, Michelle Rosenzwajg, Thomas Similowski, Yves Allenbach
Journal: Cancer Discovery (2023)

Immune-checkpoint-inhibitor (ICI)-associated myotoxicity involves the heart (myocarditis) and skeletal muscles (myositis), which frequently occur concurrently and are highly fatal. We report the results of a strategy that included identification of individuals with severe ICI myocarditis by also screening for and managing concomitant respiratory muscle involvement with mechanical ventilation, as well as treatment with the CTLA4 fusion protein abatacept and the JAK inhibitor ruxolitinib. Forty cases with definite ICI myocarditis were included with pathologic confirmation of concomitant myositis in the majority of patients. In the first 10 patients, using recommended guidelines, myotoxicity-related fatality occurred in 60%, consistent with historical controls. In the subsequent 30 cases, we instituted systematic screening for respiratory muscle involvement coupled with active ventilation and treatment using ruxolitinib and abatacept. The abatacept dose was adjusted using CD86 receptor occupancy on circulating monocytes. The myotoxicity-related fatality rate was 3.4% (1/30) in these 30 patients versus 60% in the first quartile (P < 0.0001). These clinical results are hypothesis-generating and need further evaluation. Early management of respiratory muscle failure using mechanical ventilation and high-dose abatacept with CD86 receptor occupancy monitoring combined with ruxolitinib may be promising to mitigate high fatality rates in severe ICI myocarditis. See related commentary by Dougan, p. 1040. This article is highlighted in the In This Issue feature, p. 1027.
A molecular sensitization map of European children reveals exposome‐ and climate‐dependent sensitization profiles
Authors: M. B. Gea Kiewiet, Christian Lupinek, Susanne Vrtala, Sandra Wieser, Alexandra Baar, Renata Kiss, Inger Kull, Erik Melén, Magnus Wickman, Daniela Porta, Davide Gori, Ulrike Gehring, Rob Aalberse, Jordi Sunyer, Marie Standl, Joachim Heinrich, Dagmar Waiblinger, John Wright, Josep M. Antó, Jean Bousquet, Marianne van Hage, Rudolf Valenta
Journal: Allergy (2023)

Abstract Background Understanding differences in sensitization profiles at the molecular allergen level is important for diagnosis, personalized treatment and prevention strategies in allergy. Methods Immunoglobulin E (IgE) sensitization profiles were determined in more than 2800 sera from children in nine population‐based cohorts in different geographical regions of Europe; north [BAMSE (Sweden), ECA (Norway)], west/central [PIAMA (the Netherlands), BiB (the United Kingdom), GINIplus (Germany)], and south [INMA Sabadell and Gipuzkoa (Spain) and ROBBIC Rome and Bologna (Italy)] using the MeDALL‐allergen chip. Results Sensitization to grass pollen allergen, Phl p 1, and to major cat allergen, Fel d 1, dominated in most European regions whereas sensitization to house dust mite allergens Der p 1, 2 and 23 varied considerably between regions and were lowest in the north. Less than half of children from Sabadell which has a hot and dry climate were sensitized to respiratory allergens, in particular house dust mite allergens as compared to Gipuzkoa nearby with a more humid climate. Peanut allergen Ara h 1 was the most frequently recognized class 1 food allergen in Northern/Western Europe, while the fruit allergens Pru p 3, Act d 1 and 2 were prominent in Southern and Western/Central Europe. Ves v 5‐sensitization dominated in North and West/Central Europe. Conclusion We show regional, exposome‐ and climate‐dependent differences in molecular IgE‐reactivity profiles in Northern, Western/Central and Southern Europe which may form a molecular basis for precision medicine‐based approaches for treatment and prevention of allergy.
Polyampholyte‐Based Polymer Hydrogels for the Long‐Term Storage, Protection and Delivery of Therapeutic Proteins
Authors: Robin Rajan, Nishant Kumar, Dandan Zhao, Xianda Dai, Keiko Kawamoto, Kazuaki Matsumura
Journal: Advanced Healthcare Materials (2023)

Abstract Protein storage and delivery are crucial for biomedical applications such as protein therapeutics and recombinant proteins. Lack of proper protocols results in the denaturation of proteins, rendering them inactive and manifesting undesired side effects. In this study, polyampholyte‐based (succinylated ε ‐poly‐ l ‐lysine) hydrogels containing polyvinyl alcohol and polyethylene glycol polymer matrices to stabilize proteins are developed. These hydrogels facilitated the loading and release of therapeutic amounts of proteins and withstood thermal and freezing stress (15 freeze–thaw cycles and temperatures of −80 °C and 37 °C), without resulting in protein denaturation and aggregation. To the best of our knowledge, this strategy has not been applied to the design of hydrogels constituting polymers, (in particular, polyampholyte‐based polymers) which have inherent efficiency to stabilize proteins and protect them from denaturation. Our findings can open up new avenues in protein biopharmaceutics for the design of materials that can store therapeutic proteins long‐term under severe stress and safely deliver them.